Osteoporosis is a metabolic bone disease with dysregulated coupling between bone resorption and bone formation, which results in decreased bone mineral density. The MEF2C locus, which encodes the transcription factor MADS box transcription enhancer factor 2, polypeptide C (MEF2C), is strongly associated with adult osteoporosis and osteoporotic fractures. Although the role of MEF2C in bone and cartilage formation by osteoblasts, osteocytes, and chondrocytes has been studied, the role of MEF2C in osteoclasts, which mediate bone resorption, remains unclear. In this study, we identified MEF2C as a positive regulator of human and mouse osteoclast differentiation. While decreased MEF2C expression resulted in diminished osteoclastogenesis, ectopic expression of MEF2C enhanced osteoclast generation. Using transcriptomic and bioinformatic approaches, we found that MEF2C promotes the RANKL-mediated induction of the transcription factors c-FOS and NFATc1, which play a key role in osteoclastogenesis. Mechanistically, MEF2C binds to FOS regulatory regions to induce c-FOS expression, leading to the activation of NFATC1 and downstream osteoclastogenesis. Inducible deletion of Mef2c in mice resulted in increased bone mass under physiological conditions and protected mice from bone erosion by diminishing osteoclast formation in K/BxN serum induced arthritis, a murine model of inflammatory arthritis. Our findings reveal direct regulation of osteoclasts by MEF2C, thus adding osteoclasts as a cell type in which altered MEF2C expression or function can contribute to pathological bone remodeling.

骨质疏松症是一种代谢性骨病，骨吸收和骨形成之间的耦合失调，导致骨矿物质密度降低。MEF2C _编码转录因子 MADS 盒转录增强因子 2，多肽 C (MEF2C) 的基因座与成人骨质疏松症和骨质疏松性骨折密切相关。尽管已经研究了 MEF2C 在成骨细胞、骨细胞和软骨细胞形成骨和软骨中的作用，但 MEF2C 在介导骨吸收的破骨细胞中的作用仍不清楚。在这项研究中，我们将 MEF2C 鉴定为人和小鼠破骨细胞分化的正调节因子。虽然 MEF2C 表达减少导致破骨细胞生成减少，但 MEF2C 的异位表达增强了破骨细胞的生成。使用转录组学和生物信息学方法，我们发现 MEF2C 促进 RANKL 介导的转录因子 c-FOS 和 NFATc1 的诱导，这在破骨细胞生成中起着关键作用。从机械上讲，FOS调节区域诱导 c-FOS 表达，导致NFATC1激活和下游破骨细胞生成。小鼠中Mef2c的诱导性缺失导致生理条件下骨量增加，并通过减少 K/BxN 血清诱导的关节炎（一种炎症性关节炎的小鼠模型）中的破骨细胞形成来保护小鼠免受骨侵蚀。我们的研究结果揭示了 MEF2C 对破骨细胞的直接调节，因此将破骨细胞添加为一种细胞类型，其中改变的 MEF2C 表达或功能可以促进病理性骨重塑。